Pre-Screening Inclusion Criteria:

• Women of age ≥ 18 years old.
• History of locally advanced or metastatic breast cancer that is ERα negative or low (<10% nuclear staining) and HER2 negative (see note below).
  • Note: HER2 Negative Disease per 2013 ASCO/CAP guidelines, one of the following must apply:
    • 0 or 1+ by IHC and not amplified by ISH;
    • 0 or 1+ by IHC and ISH not done;
    • 2+ by IHC and not amplified by ISH or;
    • IHC not done and not amplified by ISH.
• ≤2 prior chemotherapy regimens for treatment of metastatic breast cancer Note: Prior use of monoclonal antibodies targeting PD1, PDL1 is allowed.
• ECOG Performance status 0 or 1.
• Willing to submit a biopsy specimen from locally recurrent or metastatic site (not primary) of breast cancer for ERβ staining to Mayo Clinic Anatomic Pathology, if available; OR
• Willing to undergo biopsy during Pre-Registration phase.

Pre-Registration Inclusion Criteria:

• For patients who submitted tissue for Pre-Screening only: Presence of moderate or strong nuclear ERβ staining in >10% of cells.
• History of locally advanced or metastatic breast cancer that is ERα negative or low (<10% nuclear staining), PR negative or low (<10% nuclear staining), and HER2 neg.
  • Note:  HER2 Negative Disease per 2013 ASCO/CAP guidelines, one of the following must apply:
    • 0 or 1+ by IHC and not amplified by ISH;
    • 0 or 1+ by IHC and ISH not done;
    • 2+ by IHC and not amplified by ISH; or
    • IHC not done and not amplified by ISH.
• Willing to undergo a standard of care biopsy of locally recurrent or metastatic breast cancer for ERα, PR, and HER2 as well as additional research cores.
• Measurable or non-measurable disease as defined by RECIST criteria.
• If history of brain metastases must meet the following criteria:
  • Patients with a history of brain metastases are eligible only if they are asymptomatic and have stable disease for ≥3 months, including <28 days of prior to pre-registration;
  • Not receiving steroids for brain metastases.
• Age ≥ 18 years old.
• ECOG Performance status 0 or 1.
• Prior treatment with paclitaxel and anthracycline (in combination or in separate regimens) either in the adjuvant or metastatic setting.
• ≤ prior chemotherapy regimens for treatment of metastatic breast cancer (Note: Prior use of monoclonal antibodies targeting PD1, PDL1 is allowed).
• Women must be postmenopausal.
  • Note: Postmenopausal status is verified by:
    • Prior bilateral surgical oophorectomy; or
    • Age ≥ 60 years; or
    • Age < 60 years with no menses for >1 year with FSH and estradiol levels within postmenopausal range, according to institutional standard.
• Able to swallow oral medications.
• Willingness to stop use of strong inducers or inhibitors of CYP3A4 prior to registration.
  • Note: Use of strong inducers or inhibitors is allowed during pre-registration as long as patient will complete course prior to registration.

Pre-Registration Exclusion Criteria:

• Uncontrolled intercurrent illness including, but not limited to:
  • Ongoing or active infection;
  • Symptomatic congestive heart failure;
  • Unstable angina pectoris;
  • Uncontrolled symptomatic cardiac arrhythmia;
  • Uncontrolled hypertension (defined as blood pressure >160/90).
• Any of the following co-morbid conditions:
  • DVT/PE ≤12 months prior to pre-registration;
    • Note: Patients who are on anticoagulant therapy for maintenance are eligible as long as the DVT and /or PE occurred >6 months prior to Pre-Registration, and there is no evidence for active thrombosis (either DVT or PE).
  • Stroke ≤ months prior to pre-registration;
  • Two or more episodes of DVT and/or PE ≤ years prior to pre-registration;
  • Abnormal uterine bleeding ≤6 months prior to pre-registration;
  • History of coagulopathy.
• Other active second malignancy other than non-melanoma skin cancers within 3 years prior to pre-registration.
  • Note: A second malignancy is not considered active if all treatment for that malignancy is completed and the patient has been disease-free for ≥3 years prior to pre-registration.

Registration Inclusion Criteria:

• Histologic confirmation, from local lab that tumor is ERα negative (<1% nuclear staining), and HER2 negative, and central lab confirmation that tumor is ERβ positive (≥5% moderate or strong nuclear staining).
• Laboratory values ≤14 days prior to registration:
  • Hemoglobin ≥8 g/dL;
  • Platelet Count ≥5,000/mm3;
  • Creatinine ≤1.5 x upper limit of normal ULN;
  • Total Bilirubin ≤1.5 x upper limit of normal (ULN);
  • AST/SGOT ≤2.5 x upper limit of normal (ULN)*
    • *For patients with liver metastasis: ≤ 5 x upper limit of normal (ULN).

Registration Exclusion Criteria:

• None of the following therapies are allowed ≤4 days prior to registration*:
  • Chemotherapy;
  • Immunotherapy;
  • Biologic therapy;
  • Hormonal therapy;
  • Monoclonal antibodies;
  • Anti-HER2 or other "targeted" (e.g., mTOR) therapy.
    • *Note: Any adverse events derived from these therapies must be ≤rade 2 prior to starting study therapy (exceptions for alopecia, peripheral neuropathy).